tbuckley/cabot-search huggingface dataset:
Abstract B071: Preclinical evaluation of RM-042, an orally bioavailable inhibitor of GTP-RAS, in models of pancreatic ductal adenocarcinoma
Authors: Urszula N. Wasko, Stephen A. Sastra, Carmine F. Palermo, David Wildes, Mallika Singh, Kenneth P. Olive
Journal: Cancer Research (2022)

Abstract Approximately 95% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, accounting for over 45,000 deaths per year in the United States. In KRAS-mutant cells, KRAS protein exists predominantly in an active, GTP-bound state, leading to excessive oncogenic signaling via RAF/MEK/ERK and other effector pathways. After decades of anticipation, the first therapeutic inhibitors of this oncoprotein target a specific mutant allele (KRASG12C) and have shown promising results in this rare subset of human PDAC patients (1-2% of cases). While these encouraging clinical results bolster support for targeting RAS in human PDAC, most patients harbor KRASG12D and KRASG12V mutations and remain unserved by targeted therapies. Here we report preclinical studies of RM-042, a first-in-class, potent, oral, small molecule inhibitor of GTP-bound RAS proteins, designed to treat cancers driven by a variety of RAS mutations. RMC-6236, a clinical candidate and RM-042, a tool compound, both act through non-covalent binding to an abundant intracellular chaperone protein, cyclophilin A (CypA), resulting in a binary complex that engages GTP-bound RAS to form a high-affinity, RAS-selective tri-complex that sterically inhibits RAS binding to effectors. We examined the anti-tumor activity of RM-042 in two complementary preclinical model systems of PDAC. Using primary human PDAC explant cultures (tissue slices cultured intact in optimized media for up to one week), we found that RM-042 potently inhibits phospho-ERK expression (a marker of KRAS/RAF/MEK pathway activity), in a concentration-dependent manner. Loss of pERK expression in tumors was also associated with reduced viability, and altered stromal content. Pilot studies in the K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cretg/+ (KPC) mouse model of PDAC found that RM-042 induced tumor stabilizations and regressions associated with loss of pERK expression, and alterations in apoptosis and proliferation, at tolerated doses. Ongoing studies will determine the duration of tumor responses and assess the mechanisms by which RM-042 may impact both epithelial and stromal cell populations. Together, these studies provide complementary evidence from in vivo murine and ex vivo human models for anti-tumor activity in response to GTP-Ras inhibition, supporting the inclusion of PDAC patients in future clinical trials of RMC-6236. Citation Format: Urszula N. Wasko, Stephen A. Sastra, Carmine F. Palermo, David Wildes, Mallika Singh, Kenneth P. Olive. Preclinical evaluation of RM-042, an orally bioavailable inhibitor of GTP-RAS, in models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B071.
Abstract C078: Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer
Authors: Huocong Huang, Zhaoning Wang, Yuqing Zhang, Rachana N. Pradhan, Debolina Ganguly, Raghav Chandra, Gilbert Murimwa, Steven Wright, Xiaowu Gu, Ravikanth Maddipati, Sören Müller, Shannon J. Turley, Rolf A. Brekken
Journal: Cancer Research (2022)

Abstract Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor β. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy. Citation Format: Huocong Huang, Zhaoning Wang, Yuqing Zhang, Rachana N. Pradhan, Debolina Ganguly, Raghav Chandra, Gilbert Murimwa, Steven Wright, Xiaowu Gu, Ravikanth Maddipati, Sören Müller, Shannon J. Turley, Rolf A. Brekken. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C078.
Abstract B008: Lipocalin-2 expression modulates ferroptosis in pancreatic ductal adenocarcinoma
Authors: Valentina Pita Grisanti, Andrew W. Dangel, Maciej Pietrzak, Amy Hite, Zobeida Cruz-Monserrate
Journal: Cancer Research (2022)

Abstract Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the US. Lipocalin 2 (LCN2) is upregulated in PDAC patients and promotes inflammation and tumor growth. LCN2 regulates iron levels, which are dysregulated in tumors as cancer cells uptake increased iron to support growth. High iron levels can lead to ferroptosis, an iron-catalyzed form of cell death that relies on the oxidation of poly-unsaturated fatty acids (PUFAs). Ferroptosis is usually inhibited in cancer to prevent cell death and promote tumor growth. Therefore, LCN2 expression might influence ferroptosis outcomes in PDAC. Objective: To determine whether LCN2 inhibits ferroptosis and whether modulating LCN2 levels and other targets can be leveraged as treatments to induce ferroptosis in PDAC. Methods: Lcn2 expression was deleted via CRISPR in a mouse PDAC cell line (mKPC) to generate control Lcn2+/+ and Lcn2-/- mKPC cells. Gene expression changes were analyzed with RNA sequencing. Human and mouse PDAC cells were treated with a ferroptosis inducer, LCN2 blockade, and various PUFAs. Treatment effects on cell proliferation and lipid peroxidation were measured via 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay and BODIPY 581/591 C11 staining respectively. Gene expression of ferroptosis markers (SLC7A11, GPX4, and SLC11A2) and LCN2 were measured via RT-qPCR. Results: Deletion of Lcn2 in mKPC cells significantly decreased the expression of genes involved in ferroptosis-inhibiting antioxidant synthesis. Ferroptosis induction upregulated Lcn2 expression in PDAC cells and decreased the viability of mKPC Lcn2-/- and human PDAC cells, but not mKPC Lcn2+/+ or human pancreatic duct epithelial cells. LCN2 blockade treatment to PDAC cells modulated the expression SLC7A11, GPX4, and SLC11A2, key enablers and inhibitors of the ferroptosis antioxidant pathway. Conclusions: Ferroptosis decreases proliferation of PDAC cells, which might be mediated by LCN2 expression. LCN2 modulation has potential to induce ferroptosis and delay PDAC growth. Future studies will determine whether a combination approach with LCN2 modulation could induce ferroptosis in PDAC. Acknowledgments: This research is supported by the OSU Pelotonia Fellowship Program and the NCI R01CA223204. Citation Format: Valentina Pita Grisanti, Andrew W. Dangel, Maciej Pietrzak, Amy Hite, Zobeida Cruz-Monserrate. Lipocalin-2 expression modulates ferroptosis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B008.
Abstract B018: Eosinophils alter metastatic spread in pancreatic cancer
Authors: Megan T. Hoffman, Patrick J. Lenehan, Jennifer Wang, Lestat Ali, Li Qiang, Amiko Uchida, Sara Vayrynen, Andressa Dias Costa, Michael Dougan, Max Heckler, Jonathan Nowak, Brian W. Wolpin, Stephanie K. Dougan
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the US with a 11% 5-year survival rate. A key contributor of this dismal prognosis is early and frequent metastatic spread with limited treatment options for patients. Metastasis in PDA is facilitated by a robust fibroinflammatory response in the primary tumor site, a large portion of which is composed of infiltrating immune cells, and survival during transit to establish in the secondary site. In the primary tumor reactive stroma, we found increased eosinophils in both human and mouse PDA compared to the normal pancreas. Eosinophils are an innate immune cell best known for their ability to control parasite responses and have been implicated in either pro- or anti-cancer roles in various solid tumors. We used the ΔdblGata mice, which lack eosinophils, to study the role of eosinophils during metastatic spread using a resectable model of PDA metastasis. This model of metastasis was developed to facilitate consistent seeding of lung metastasis in approximately 50 percent of mice from a transient subcutaneous tumor which undergoes subsequent surgical removal and harvest to evaluate metastasis at 4 weeks. We found that mice lacking eosinophils have increased metastasis to the lung in our resectable model of PDA metastasis but no difference in establishment of IV injected PDA tumor cells, suggesting eosinophil control at the primary tumor site. Single cell sequencing of the subcutaneous tumors finds differences in the angiogenic subtypes, tip and stalk cells, in mice lacking eosinophils. Sequencing of eosinophil populations in humans and mice find an increase in angiogenic signaling suggesting a regulatory role in tumor cell access to the circulation. We conclude that eosinophils in PDA inhibit the metastatic process through control of angiogenic signaling. Citation Format: Megan T. Hoffman, Patrick J. Lenehan, Jennifer Wang, Lestat Ali, Li Qiang, Amiko Uchida, Sara Vayrynen, Andressa Dias Costa, Michael Dougan, Max Heckler, Jonathan Nowak, Brian W. Wolpin, Stephanie K. Dougan. Eosinophils alter metastatic spread in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B018.
From liver fibrosis to hepatocarcinogenesis: Role of excessive liver H2O2 and targeting nanotherapeutics
Authors: Meiyu Shao, Yifan Wang, Hongyan Dong, Lu Wang, Xiaoqing Zhang, Xin Han, Xianan Sang, Yini Bao, Mengyun Peng, Gang Cao
Journal: Bioactive Materials (2022)

Liver fibrosis and hepatocellular carcinoma (HCC) have been worldwide threats nowadays. Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage. In pathological liver, excessive H2O2 is generated and accumulated, which impacts the functionality of hepatocytes, Kupffer cells (KCs) and hepatic stellate cells (HSCs), leading to genesis of fibrosis and HCC. H2O2 accumulation is associated with overproduction of superoxide anion (O2•-) and abolished antioxidant enzyme systems. Plenty of therapeutics focused on H2O2 have shown satisfactory effects against liver fibrosis or HCC in different ways. This review summarized the reasons of liver H2O2 accumulation, and the role of H2O2 in genesis of liver fibrosis and HCC. Additionally, nanotherapeutics targeting H2O2 were summarized for further consideration of antifibrotic or antitumor therapy.
Evaluating complete remission with partial hematologic recovery (CRh) as a response criterion in myelodysplastic syndromes (MDS)
Authors: Andrew M. Brunner, Alexander Gavralidis, Najla Al Ali, Anthony Hunter, Rami Komrokji, Amer Zeidan, David A. Sallman
Journal: Blood Cancer Journal (2022)

Myelodysplastic syndromes (MDS) treated with DNMTI therapy have responses according to the 2006 IWG response criteria. CR responses have had the strongest association with OS. Recently, CR with partial hematologic recovery (CRh; i.e. blasts &lt;5%, ANC &gt; 500, platelets &gt; 50) has been evaluated in AML, but its relevance is unknown in MDS. We identified adult patients with MDS treated with DNMTIs. We assessed best overall response to therapy according to IWG 2006 criteria, and subsequently identified patients meeting CRh criteria from the subgroup with SD or mCR. We evaluated duration of therapy and overall survival according to response. We identified 311 patients with MDS who received treatment between 2007 and 2018. The median age at the time of therapy was 69 years (range 23-91). Median follow up was 60 months. According to IWG 2006, responses included CR (n = 43, 14%), PR (n = 2, 1%), mCR (n = 57, 18%), SD (n = 149, 48%) and PD (n = 60, 19%). 79 patients (25%) achieved HI. A total of 62 patients (20%) met CRh criteria leading to reclassification of mCR (now n = 26, 8%) or SD (now n = 118, 38%). Patients achieving CR had similar time on therapy (median 8.1mo) compared to CRh (median 6mo, HR 1.4, 95% CI 0.9-2.0), and longer than other responses (p &lt; 0.001). OS varied according to response; median OS was similar between CR (23.3mo) and CRh (25mo, HR 1.28 [0.79-2.08]), which was longer than those with mCR (17.2mo, HR 1.71 [0.96-3.05]), SD (16.3mo, HR 1.61 [1.04-2.48]), and PD (8.7mo, HR 3.04 [1.91-4.83]) (p &lt; 0.001). OS associations with CR/CRh were confirmed in multivariable analysis accounting for allogeneic transplant. MDS patients who achieve a CRh response had similar survival and duration on therapy as patients who achieve CR response and superior to other IWG responses. These data support further evaluation of CRh into future response criteria and clinical trials.
Abstract C079: Aberrantly exposed phosphatidylserine as a drug delivery target in pancreatic cancer
Authors: Natalie Z. Phinney, Xianming Huang, Rolf Brekken
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) has risen to become the 3rd leading cause of cancer related deaths in the United States with a 5-year survival rate of 11% and a median survival of just 4-6 months. PDA is notoriously chemoresistant and has shown little to no sensitivity to the current immune checkpoint blockade therapy. A novel marker for the tumor microenvironment that has emerged is phosphatidylserine, initially characterized as a selective marker of tumor vasculature. Phosphatidylserine (PS) is a phospholipid exposed on the outer leaflet of the plasma membrane of tumor associated endothelial cells, apoptotic tumor cells, and some viable tumor cells, where it functions to suppress the immune response. Exposed PS drives immunosuppression by binding to PS receptors expressed on tumor-infiltrating macrophages and dendritic cells. To this point, PS has been targeted with antibodies, such as Bavituximab, that have shown excellent specificity for tumor vasculature and an immune stimulatory environment evidence by polarization of macrophages to a pro-inflammatory M1-like phenotype, a reduction in myeloid-derived suppressor cells, enhanced maturation of dendritic cells and increased primed T cell activity. We have advanced this concept by developing the next generation of PS targeting agent, a fusion protein (betabody) that exploits the PS-binding domain of β2-glycoprotein 1 (β2GP1), an abundant serum protein that binds PS. Betabodies were constructed by fusing domain V of β2GP1 to the Fc of an IgG2a. Betabodies are smaller than full length antibodies (~85 kDa vs 150 kDa), have good affinity for PS (~1 nM) and bind directly to PS. We have demonstrated that betabodies bind specifically to externalized PS through ELISA, ICC and flow cytometry. We established that betabodies localize robustly and specifically to the tumor microenvironment through in vivo localization experiments in tumor-bearing C57Bl/6 mice. Further studies will exploit the specificity of betabodies to deliver novel microtubule-disrupting agents to exposed PS in the microenvironment of PDA. Due to the fact that betabodies are internalized inefficiently, therapeutic payloads will be linked to betabodies via enzyme cleavable linkers. This first-in-class tumor targeting therapeutic has potential to provide efficacy in therapy-resistant pancreatic tumors. Citation Format: Natalie Z. Phinney, Xianming Huang, Rolf Brekken. Aberrantly exposed phosphatidylserine as a drug delivery target in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C079.
Abstract PR011: Proteomic profiling reveals subtype specific kinase expression in pancreatic cancer
Authors: Yi Xu, Ashley B. Morrison, Silvia G. Herrera, Michael P. East, Gary L. Johnson, Jen Jen Yeh
Journal: Cancer Research (2022)

Abstract We have previously identified two tumor specific molecular subtypes in pancreatic ductal adenocarcinoma (PDAC), basal-like and classical. Although basal-like tumors are found in less than 20% of patients, patients with basal-like tumors have a worse prognosis and are largely resistant to FOLFIRINOX chemotherapy. To identify targetable basal-like subtype specific vulnerabilities in PDAC, we utilized Multiplexed kinase Inhibitor Beads and Mass Spectrometry (MIB-MS) to profile the kinome in patient derived xenograft (PDX) models that recapitulate the tumor subtypes found in patients. MIB-MS results show that kinase expression is significantly associated with molecular subtype. Notably, basal-like tumors show increased expression of receptor tyrosine kinases (RTKs) including EGFR, MET, and IGF1R and MAP kinase members MEK2 and BRAF indicating activation of the MAP kinase signaling cascade. These RTKs including EGFR are also differentially expressed in primary patient tumors suggesting the true efficacy of EGFR and other kinase inhibitors in basal-like tumors may have been masked by the larger proportion of patients (&amp;gt;80%) with unresponsive classical tumors. Furthermore, inhibition of MAP kinase signaling with the MEK inhibitor trametinib results in kinome reprogramming exclusive to classical tumors. MIB-MS profiling reveals upregulation of TAOK3 and MEK3/6 indicating activation of p38 MAP kinase signaling as a classical subtype specific compensatory mechanism against MEK inhibition. Overall, these results present actionable basal-like subtype specific kinase targets by defining a novel subtype specific kinome in PDAC. Precision approaches in clinical trials are needed to determine if new and previously thought to be disappointing kinase inhibitors may be efficacious in patients with basal-like tumors. Citation Format: Yi Xu, Ashley B. Morrison, Silvia G. Herrera, Michael P. East, Gary L. Johnson, Jen Jen Yeh. Proteomic profiling reveals subtype specific kinase expression in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR011.
Abstract C010: Polymerase theta inhibition synergizes with anti-PD-1 immunotherapy in BRCA2-deficient pancreatic ductal adenocarcinoma
Authors: Jeffrey Patterson-Fortin, Heta Jadhav, Constantia Pantelidou, Tin Phan, Carter Grochala, Jie Hao, Junning Wang, Elizabeth A. Andrews, Jennifer L. Guerriero, Brian M. Wolpin, Ben Z. Stanger, Andrew A. Aguirre, James M. Cleary, Alan A. D'Andrea, Geoffrey I. Shapiro
Journal: Cancer Research (2022)

Abstract Recently developed inhibitors of polymerase theta (POLQ) have demonstrated synthetic lethality in pre-clinical tumor models of BRCA1 and BRCA2-deficient cancers. Since other DNA repair inhibitors, including PARP inhibitors, induce changes in the tumor immune microenvironment (Pantelidou et al., Cancer Discovery, 2019), we asked whether POLQ inhibition would cause similar alterations in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Initially, we generated BRCA2-deficient cells by CRISPR-mediated deletion of the BRCA2 gene in a murine KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx1-Cre;Rosa26YFP/YFP (KPCY) PDAC cell line (Li et al., Immunity, 2018). Injection of these cells into syngeneic mice generated an aggressive immunocompetent BRCA2-deficient tumor model. We next demonstrated that novobiocin (NVB), a first-in-class inhibitor of the POLQ ATPase domain (Zhou et al., Nature Cancer, 2021), induces both innate and adaptive immune responses in this model through activation of the cGAS/STING pathway. NVB exposure resulted in upregulation of micronuclei, increased cGAS/STING pathway activation, increased type I interferon expression, increased CD8+ T-cell infiltration, and local paracrine activation of dendritic cells. NVB-mediated POLQ inhibition also upregulated PD-L1 expression, correlating with increased cGAS/STING pathway activation. These NVB-induced changes were associated with antitumor activity. Whereas depletion of CD8+ T-cells compromised the efficacy of NVB, the antitumor effects of POLQ inhibition were augmented when combined with anti-PD-1 immunotherapy. Taken together, our findings demonstrate that NVB-mediated POLQ inhibition induces immune responses in a cGAS/STING-dependent manner and provides a rationale for combining POLQ inhibition with immune checkpoint blockade for the treatment of BRCA2-deficient pancreatic cancers. Citation Format: Jeffrey Patterson-Fortin, Heta Jadhav, Constantia Pantelidou, Tin Phan, Carter Grochala, Jie Hao, Junning Wang, Elizabeth A. Andrews, Jennifer L. Guerriero, Brian M. Wolpin, Ben Z. Stanger, Andrew A. Aguirre, James M. Cleary, Alan A. D'Andrea, Geoffrey I. Shapiro. Polymerase theta inhibition synergizes with anti-PD-1 immunotherapy in BRCA2-deficient pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C010.